Cocaine is thought to produce many of its effects through an interaction with dopaminergic neuronal systems. Cocaine's neurochemical effects may include modifications in the numbers of receptors or uptake sites for dopamine (DA) or other regulatory peptides colocalized with DA, such as neurotensin (NT). If such changes occur, it is not known if they are permanent. Thus, we treated rats with programmed infusions of isotonic saline or 1 mg/kg cocaine every 12 min for 2 hr over 10 days and killed them within 15 min of the last infusion. Other rats were treated identically, but were killed 10 days later. Brains were removed and immediately frozen. Ten micron sections were taken through areas known to contain DA perikarya or terminals and binding experiments were conducted on the slices to determine the loci and number of binding sites for NT, and desmethylimipramine-insensitive mazindol binding sites to mark the DA transporter. Additional sections were taken for analysis of binding of paroxetine, and corticotropin releasing hormone. Analysis for NT sites is complete at this time. We found that cocaine reduced NT binding sites in the ventral tegmental area, substantia nigra and pars lateralis and that these reductions were reversed 10 days later. In addition, NT binding in the prefrontal cortex of rats killed within 15 minutes of their final infusion of cocaine was twice that of saline-treated rats and these sites were increased by an additional 50% ten days after withdrawal of cocaine. In contrast, the binding of DA uptake sites was not changed at the end of the period of cocaine administration, but was reduced in the nucleus accumbens ten days after withdrawal of cocaine. The persistent up-and down-regulation of these receptors may be intimately involved in the long-lasting behavioral and psychological effects associated with the use of cocaine and abstinence from it.